Study Abstract Hypotheses: that designer T cells offer an immune based alternative to cancer therapies that has the potential to cure metastatic breast cancers; that several components will potentially contribute to an optimal therapeutic anti-tumor agent; that CEA is the optimal platform for a rapid optimization that will allow generalizable lessons over the range of breast cancer antigens.

Researcher Paul Goodfellow, PhD, The Ohio State University College of Medicine, Columbus, OH, and Jennifer Ivanovich, MS, Washington University School of Medicine, St. Louis, MO

Study Abstract Breast cancer takes its greatest toll on young women. Young women frequently have biologically aggressive tumors. They often present with advanced disease and their tumors are frequently hormone non- responsive, thereby limiting treatment options. Young women suffer lower than average disease-free and overall survival. The work proposed is focused on discovery of the as yet unknown genetic risk factors that underlie development of early-onset breast cancer. These findings will pave the way for future studies to elucidate how genetic risk and environmental factors interact and account for the aggressive tumors and poor outcome young breast cancer patients experience. We hypothesize copy number variants (CNVs) play an important role in risk for development of early-onset breast cancer.

Study Abstract We intend to study the role of the gastrointestinal (GI) microbiota in the pathogenesis of breast cancer (BC) in women. Humans are super organisms that represent a fusion of eukaryotic cells of their own, as well as bacteria and archaea that reside in and over the body, primarily in the GI tract. Little is known about the GI microbiota, which represents the most dense and least diverse ecosystem known on earth. It is believed that GI microbiota is passed on from the mother to her infants and remains fairly stable through life. Bacterial cells in the GI tract outnumber human cells in the body by about 10 fold and carry thousands of additional genes which can rapidly evolve under the pressure of changing environmental factors. The GI tract microbiota approximately weighs about 1 kg in a human being and is estimated to have a metabolic activity comparable to the human liver. A recent metagenomic survey of this activity shows that the bacterial genes for xenobiotics (important in carcinogen and hormone metabolism) are enhanced in the human GI tract.

Study Abstract The objective of this trial is to test whether a low dose of tamoxifen can have a beneficial effect on breast cancer risk biomarkers in women treated with chest radiotherapy for a prior diagnosis of cancer. Such women have a very high risk of developing breast cancer, approximately 55-times that of an average woman. The standard daily dose of 20mg of tamoxifen has been shown to decrease breast cancer risk by 50%. More recent data suggest that a lower dose of 5mg daily has a similar beneficial effect but with lower side effects. The Low Dose Tamoxifen Breast Cancer Risk Reduction Trial is a placebo-controlled randomized controlled trial of tamoxifen delivered at a reduced dose of 5mg daily for two years. The study is also measuring the safety and tolerability of tamoxifen at the lower dose.

Study Abstract Depressive disorders and symptoms are prevalent in patients with breast cancer, worsen over the course of cancer treatment, persist after cancer therapy, significantly impair quality of life, and decrease adherence to cancer therapy and survival. Yet, there are no established treatments for depression in breast cancer patients. As surviving cancer becomes increasingly common, there is an urgent need to develop an empirical basis to provide effective, evidence-based treatments to this population.

We are conducting a randomized clinical trial to compare the efficacy of Interpersonal Psychotherapy (IPT), Problem-Solving Therapy (PST), and Brief Supportive Psychotherapy (BSP) in alleviating depressive symptoms and improving quality of life for breast cancer patients with DSM-IV major depressive disorder (MDD). In addition to improvement in depressive symptoms, relationships between sociodemographic characteristics, clinical factors, depression treatment adherence, and outcomes care will be examined. Patients in each condition will receive 12 therapy sessions within a 16-week period, and will be followed for another 4 months to examine the stability of response.

Researcher Harry Ostrer, MD, Albert Einstein College of Medicine, Bronx, New York

Study Abstract Genome wide association studies (GWAS) of breast cancer risk have provided clues for the identification of other risk genes. Single nucleotide polymorphisms (SNPs) in or near the FGFR2, TNRC9, MAP3K1, LSP1 and CASP genes, in addition to a presumed regulatory region upstream from the C-MYC gene on chromosome 8q24 and on 2q have been studied in several populations. An alternative approach would be to identify the rare but high-penetrant alleles that are not captured by GWAS. This approach has been successful when applied to studying the tails of the risk distribution for blood pressure and cardiac phenotypes. Recognizing the importance of this approach, the National Heart, Lung and Blood Institute established the Exome Sequencing Project (ESP) to study the tails of the distributions for diseases that fall within their mission. Exome sequencing offers the advantage of surveying key regions of the expressed regions, rather than the entire, genome, thus reducing complexity and cost. The ESP strategy can be applied by analyzing DNA for a well-defined high-risk phenotype (≥3 women affected with premenopausal breast cancer – likely to have a heritable mutation, or early onset breast cancer with no family history – likely to have a de novo mutation) and by studying well-defined populations that are likely to have common founder alleles.

Study Abstract In this proposal, we will focus on breast cancer in Hispanic women. Although Hispanics represent the fastest growing ethnic population in the U.S., they have been largely understudied in terms of genetic susceptibility to cancer even though breast cancer is the most common cancer and causes the most cancer deaths in Hispanic women. The overall long-term goal of this project is the development of a comprehensive clinical genetic test that provides a set of susceptibility genes for inherited breast cancer and can be readily integrated into clinical practice. Specific Aim 1 is to identify variants in 605 genes involved in DNA damage response pathways using next-generation sequencing. We will use DNA from 1000 Latina breast cancer patients and 1000 healthy Latina controls. Specific Aim 2 is to identify the set of variants of biological significance through in silico analyses. Specific Aim 3 is to perform gene-based association tests of the genes and risk to develop breast cancer. We will utilize Hispanic breast cancer cases already participating in Dr. Jeffrey Weitzel’s study. We will recruit Hispanic controls from the Army of Women, focusing on women from California and the Southwest United States. We expect that the results will reveal which genes are important for susceptibility to breast cancer and can be used for possible risk prediction, and provide a number of specific targets for developing therapeutics

Project Title A Pilot Study of the Flaxseed Effects on Hormones and Lignans: Role of Race, Genes, and Gut Microbiome

Researcher Susan McCann, PhD, Roswell Park Cancer Institute

Study Abstract The objective of this study is to determine how variation in gut microbial
community composition and in steroid hormone and xenobiotic metabolizing genes affects the metabolism of mammalian lignans and steroid hormones at baseline and after exposure to a lignan-rich food (flaxseed), and how these associations differ for African American and Caucasian women. Humans are, in fact, superorganisms with a diverse genetic background that is augmented by diverse and metabolically active bacterial communities, the composition of which can be modified by specific dietary exposures. The central hypothesis is that the metabolic response to a dietary component results from the combined effects of an individual’s genetic makeup and the particular composition of that individual’s gut bacterial communities. Elucidation of interactions between the gut microbiome, host genetics, and diet will have a positive impact on development of improved targeted dietary interventions to reduce cancer risk.

Project Title Acupuncture for Joint Symptoms in Women with Early Stage Breast Cancer

Researcher Southwest Oncology Group, (SWOG)

Study Abstract The primary objective of this study is to determine whether true acupuncture administered twice weekly for 6 weeks (8-12 sessions) compared to sham acupuncture and waitlist control causes a significant reduction in joint pain/stiffness related to aromatase inhibitors (AIs) in women with early stage breast cancer as measured by the Brief Pain Inventory-Short Form (BPI-SF) worst pain score at 6 weeks.

Secondary objectives are to investigate the effects of true acupuncture administered twice weekly for 6 weeks (8-12 sessions) followed by 6 weekly treatments (4-6 sessions) of maintenance (12-18 sessions total over 12 weeks) compared to sham acupuncture and waitlist control in this study population. The evaluations at 12 and 24 weeks are to determine the benefit of additional 6 weekly acupuncture treatments for maintenance and to determine the durability of response after stopping acupuncture, respectively. The evaluation at 52 weeks is to determine the long-term effects of acupuncture and adherence to AIs.

Study Abstract Mammographic breast density is one of the strongest and most consistent risk factors known for the development of breast cancer. Studies have reported a 2- to 4- fold increase in the risk of breast cancer among women with mostly dense breasts compared to women with less dense breasts. Several studies have observed racial/ethnic differences in the distribution of mammographic breast density across White, African-American and Asian women in the U.S. However, very little is known about the distribution of mammographic breast density among first- and second- generation African women residing in the US. This is a population of women that has been understudied as a separate racial/ethnic category, and often categorized together with African American women. There are important cultural and lifestyle differences that are relevant for breast cancer development that may be different between first- and second-generation African and African-American women. These are factors which, together with other biological and genetic features, may also significantly influence the patterns of mammographic density. In addition, despite a large body of cross-sectional studies of mammographic density, few studies have considered repeated measures of density, and the determinants of changes in breast density are not well understood. This study would add to the existing literature by examining breast density patterns among African immigrants and associated risk factors, and assess if these risk factors are associated with changes in breast density patterns over time.

Project Title A Study to Identify Predictors of Response to Duloxetine in Breast Cancer Patients with Chronic Pain (HUM00075181)

Researcher Norah Henry, University of Michigan, MD, PhD

Study Abstract The overall goal of this study is to learn more about why some breast cancer survivors develop chronic pain following treatment, in order to better manage their symptoms and improve their quality of life. In this proposal, the research team will investigate if some breast cancer survivors who develop chronic pain have centralized pain, since this could potentially influence treatment recommendations. This question will be addressed in two ways: 1) questionnaires to learn more about the symptoms the patients are experiencing, especially pain, fatigue, sleep disturbances, and memory problems, and 2) pain testing to determine each patient’s pain sensitivity. The research team will then treat the patients on a randomized, blinded clinical trial with duloxetine followed by placebo, or vice versa, in order to identify factors that predict which patients are more likely to benefit from duloxetine therapy. Patients will be assessed before and after each treatment using the methods described above. The hypothesis is that the patients with a greater degree of centralized pain will benefit more from treatment with duloxetine.

Study Abstract The research team proposes to conduct a single arm 2-stage Phase 2 trial of neratinib in metastatic but HER2 non-amplified but HER2 mutant breast cancer. Pre-registration is required for tumor HER2 sequencing. The primary objective is clinical benefit rate (CBR: rate of complete response plus partial response and stable disease > 6 months). With an 80% power and a 1-sided 0.05 significance level, the first stage of 10 patients and the 2nd stage of 19 patients are planned to test an anticipated CBR of 20% versus the null hypothesis of 5%. Secondary endpoints include progression free survival and the molecular epidemiology of HER2 mutation. Exploratory endpoints include mechanisms of treatment resistance and other somatic mutations in HER2 negative disease. Because the mutation frequency is approximately 2%, they anticipate screening of 1500 patients to identify the 29 patients with the HER2 mutation and eligible for study drug therapy. The success of this trial could establish a new treatment option for a subset of patients with HER2 non-amplified tumors.

Study Abstract High and rapidly increasing incidence rates of breast cancer among California Asian Americans (AA) have been masked by rates that are traditionally reported for AAs as an aggregated group. Not only do rates vary considerably among AA ethnic subgroups, the research team recently showed that they are high among young US-born women, and rapidly increasing among some US-born and foreign-born groups; for some, rates were even higher than among non-Hispanic white women in California.

The research team will recruit AA controls from the same source population to form a population-based case-control study of breast cancer risk, thereby creating a unique multilevel dataset that will allow them to address the following specific aims: to determine, among controls, 1) the associations between perceived stress and the immigration experience and discrimination, and how these associations are modified by generational status, timing of immigration, and coping styles; 2) how other relevant breast cancer exposures, including age-specific markers of infectious disease exposures, physical activity and body size, and dietary intake and behaviors, vary with generational status and timing of immigration; 3) the extent to which the factors in Aims 1 and 2 vary according to family, social network, and neighborhood characteristics and relationships; and 4) among cases and controls, identify the associations between the factors in Aims 1 and 2 and breast cancer risk among AAs.